This K24 Mid-Career Investigator in Patient-Oriented Research Award application is to support the continue development of Dr. John E. Nestler as a clinical investigator and research mentor. Dr. Nestler is Professor of Medicine at Virginia Commonwealth University's Medical College of Virginia, and has been a productive patient- oriented researcher whose research focus has been the pathophysiologic role of insulin resistance in the polycystic ovary syndrome (PCOS), a disorder that affects 6-10% of women of childbearing age. Dr. Nestler also has an established track record of mentorship of young clinical investigators. The broad long-term objective of Dr. Nestler's studies has been to conduct both mechanistic and translational studies exploring the role of insulin resistance in PCOS. The specific studies proposed in this application, which are currently funded by an NIH R0l grant and a U54 grant, are designed 1) to determine the effects of chronic insulin reduction on rates of spontaneous and clomiphene-induced ovulation in women with PCOS who were previously found to be refractory to clomiphene induction; 2) to determine whether reducing the serum insulin concentration beneficially influences gonadotropin secretory dynamics (i.e., decreases luteinizing hormone pulse amplitude and/or pulse frequency) in obese and/or lean women with PCOS; and 3) to explore whether insulin resistance causes an adverse cardiovascular risk profile in postmenopausal women with a history of PCOS during the premenopausal period. These studies will be conducted on the General Clinical Research Center using state-of-the-art methodologies, such as every 10 minute blood sampling for hormone pulse analysis by Cluster, Deconvolution Analysis and Approximate Entropy, and Reaven's steady-state plasma glucose (SSPG) technique for longitudinally monitoring insulin sensitivity. The K24 award will facilitate the completion of these studies, while also making it possible for Dr. Nestler to enhance his personal growth as a clinical investigator and to increase his mentoring activities. It will do so by providing Dr. Nestler with increased protected time, resulting from a decrease in administrative duties and clinical service responsibilities. As a result of the K24 award, Dr. Nestler will be able to devote 80% effort to research, further personal training in clinical research, and the training and mentorship of young investigators.